We have designed neuronal Protective Nanoparticles (Pro-NPs) with a unique composition containing antioxidant enzymes that are released in active form over a sustained period of time. Our goal is to test their efficacy for treating acute spinal cord injury (SCI). Disability due to SCI is a major global health issue, affecting mainly the young population. Nearly 1.3 million people in the US are living with paralysis due to SCI, and it costs $40.5 billion annually for their care. At present, there is no effective treatment that can achieve functional recovery following SCI. The pathophysiology of traumatic SCI involves the initial physical impact, which leads to secondary injury cascades of degenerative cellular and molecular events. The secondary injury spreads along the spinal cord over time, which adds new levels of disability and has devastating effects. Reactive oxygen species (ROS) formation at the impact site is an important component of these secondary injury cascades. We hypothesize that efficient and sustained delivery of antioxidants to the lesion site could alleviat the oxidative stress-mediated degenerative events following SCI and promote endogenous neuronal repair mechanisms, leading to recovery of locomotors, neurological, and physiological functions. In preliminary studies in a thoracic rat model of traumatic SCI, we demonstrated that following intravenous administration at 3 hr. post-injury, Pro-NPs pass through the disrupted blood-spinal cord barrier and localize in the lesion cavity and are significantly effective in restoring locomotors functions with a single dose whereas control animals (untreated, enzymes alone or empty NPs) remain paraplegic. Our main objectives in this proposal are both translational and basic, and are a) to demonstrate robust preclinical efficacy with Pro-NPs under clinically relevant conditions in the above animal model of SCI and b) to improve our mechanistic understanding of the treatment, particularly to determine how Pro-NPs inhibit the secondary injury cascade and promote endogenous neuronal repair mechanisms. The specific aims are: AIM 1: Delineate parameters critical for Pro-NP delivery to the lesion site. AIM 2: Determine functional recovery following treatment. AIM 3: Understand the repair mechanisms at molecular and cellular levels. If we validate our hypothesis, the most significant result of our study would be a better mechanistic understanding of neuronal repair facilitated with Pro-NPs that could also have potential impact in treating other traumatic CNS injuries.